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WO2009018367A2 - Nouvelles formes de sels de (2s)-(4e)-n-méthyl-5-[3-(5-méthoxypyridin)yl]-4-pentén-2-amine - Google Patents

Nouvelles formes de sels de (2s)-(4e)-n-méthyl-5-[3-(5-méthoxypyridin)yl]-4-pentén-2-amine Download PDF

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Publication number
WO2009018367A2
WO2009018367A2 PCT/US2008/071631 US2008071631W WO2009018367A2 WO 2009018367 A2 WO2009018367 A2 WO 2009018367A2 US 2008071631 W US2008071631 W US 2008071631W WO 2009018367 A2 WO2009018367 A2 WO 2009018367A2
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WO
WIPO (PCT)
Prior art keywords
acid
methyl
pain
amine
penten
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PCT/US2008/071631
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English (en)
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WO2009018367A3 (fr
Inventor
Gary Maurice Dull
Julio A. Munoz
John Genus
Balwinder Singh Bhatti
Jennifer A. Young
Merouane Bencherif
John W. James
Michael G. Williams
Kristen Jordan
Patrick M. Lippiello
Beth Fordham-Meier
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Targacept, Inc.
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Publication of WO2009018367A2 publication Critical patent/WO2009018367A2/fr
Publication of WO2009018367A3 publication Critical patent/WO2009018367A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • the present invention relates to novel salt forms of (2S)-(4E)-N-methyl-5-[3- (5-methoxypyridin)yl]-4-penten-2-amine and to pharmaceutical compositions including the salt forms.
  • the present invention also relates to methods for treating a wide variety of conditions and disorders, and particularly pain and conditions and disorders associated with dysfunction of the central and autonomic nervous systems, using the novel salt forms.
  • the compound (2S)-(4E)-N-methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2- amine is a neuronal nicotinic receptor (NNR) agonist with selectivity for the ⁇ 4 ⁇ 2 nicotinic subtype over other nicotinic subtypes, for example, the ⁇ 7 subtype, the ganglionic, and the muscle subtypes.
  • NNR neuronal nicotinic receptor
  • (2S)-(4E)-N-Methyl-5-[3-(5-methoxypyridin)yl]- 4-penten-2-amine provides benefits in the treatment or prevention of central nervous system (CNS) disorders and pain.
  • compositions containing the drug substance should preferably be capable of being effectively stored over appreciable periods of time, without exhibiting a significant change in the active component's physicochemical characteristics, including but not limited to, its chemical composition, water content, density, hygroscopicity, and solubility. Moreover, there is a preference to provide drug in a form, which is as chemically pure as possible. Acid addition salts of basic drugs can offer advantages in stability and purity, but these salts vary greatly in their ability to impart these properties.
  • salts of basic drugs can vary.
  • Some salts are solids at ambient temperatures, namely, those temperatures which would typically characterize preparation, storage, and use.
  • Other salts are liquids, including, viscous oils and gums, at ambient temperatures.
  • Salt forms of (2S)-(4E)-N-methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2-amine are disclosed in published PCT applications WO 02/05798 and WO 06/053039, each of which is incorporated by reference. Nevertheless, there is a need for alternative salt forms of (2S)-(4E)-N-methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2-amine with improved properties, including purity, stability, solubility, and bioavailability. Further preferential characteristics include those that would increase the ease or efficiency of manufacture of the active ingredient and its formulation into a commercial product. Furthermore, stable polymorphic forms of these salts would allow for an increase the ease or efficiency of manufacture of the active ingredient and its formulation into a commercially product.
  • the present invention includes novel forms of (2S)-(4E)-N-methyl-5-[3-(5- methoxypyridin)yl]-4-penten-2-amine with unexpected properties.
  • the invention also includes a scalable synthesis of (2S)-(4E)-N-methyl-5-[3-(5-methoxypyridin)yl]-4- penten-2-amine, suitable for large scale manufacture.
  • One aspect of the present invention includes (2S)-(4E)-N-methyl-5-[3-(5- methoxypyridin)yl]-4-penten-2-amine or a pharmaceutically acceptable salt thereof in polymorphic form.
  • Another aspect of the present invention includes a solid acid addition salt of (2S)-(4E)-N-methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2-amine, wherein the acid is selected from hydrochloric acid, sulfuric acid, maleic acid, phosphoric acid, pamoic acid, xinafoic acid, galactaric acid, L-tartaric acid, hippuric acid, fumaric acid, citric acid, D-glucuronic acid, L-malic acid, D-gluconic acid, L-ascorbic acid, p- hydroxybenzoic acid, stearic acid, lactobionic acid, orotic acid, R-mandelic acid, S- mandelic acid, oxalic acid, or hydrobromic acid, or a hydrate or solvate thereof.
  • the acid is selected from hydrochloric acid, sulfuric acid, maleic acid, phosphoric acid, pamoic acid, xinafoic acid, galacta
  • the salt has a stoichiometry of acid to (2S)-(4E)-N-methyl-5-[3-(5- methoxypyridin)yl]-4-penten-2-amine of 1 :2, 1 :1 , or 2:1.
  • the salt has a stoichiometry of acid to (2S)-(4E)-N-methyl-5-[3-(5-methoxypyridin)yl]- 4-penten-2-amine of 1:1.
  • Another aspect of the present invention includes a hydrochloric acid, maleic acid, phosphoric acid, pamoic acid, xinafoic acid, fumaric acid, galactaric acid, p- hydroxybenzoic acid, stearic acid, orotic acid, R-mandelic acid, S-mandelic acid, oxalic acid, or hydrobromic acid salt of (2S)-(4E)-N-methyl-5-[3-(5- methoxypyridin)yl]-4-penten-2-amine, or a hydrate or solvate thereof, in substantially crystalline form.
  • Another aspect of the present invention includes (2S)-(4E)-N-methyl-5-[3-(5- methoxypyridin)yl]-4-penten-2-amine hemi-galactarate or a hydrate or solvate thereof.
  • Another aspect of the present invention includes (2S)-(4E)-N-methyl-5-[3-(5- methoxypyridin)yl]-4-penten-2-amine phosphate or a hydrate or solvate thereof.
  • Another aspect of the present invention includes a polymorphic form of (2S)- (4E)-N-methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2-amine phosphate characterized by a powder x-ray diffraction pattern comprising at least one of the following peaks
  • the present invention include a polymorphic form of (2S)-(4E)-N- methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2-amine phosphate whose XRPD pattern substantially corresponds to that shown in one or more of Figures 13, 14, or 15.
  • the present invention includes a polymorphic form of (2S)-(4E)-N-methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2-amine phosphate whose XRPD pattern substantially corresponds to that shown in Figure 15.
  • Another aspect of the present invention includes Form 3 of (2S)-(4E)-N- methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2-amine phosphate.
  • Another aspect of the present invention includes a pharmaceutical composition comprising a compound of the present invention and one or more pharmaceutically acceptable diluent, excipient, or carrier.
  • Another aspect of the present invention includes a compound or pharmaceutical composition according to the present invention for use in therapy.
  • Another aspect of the present invention includes use of a compound of the present invention in the manufacture of a medicament for the treatment or prevention of a central nervous system disorder.
  • Another aspect of the present invention includes a method of treating or preventing a central nervous system disorder, comprising administering a compound or pharmaceutical composition of the present invention.
  • One embodiment of the compound, use, or method aspects of the present invention includes therapy of age-associated memory impairment, mild cognitive impairment, pre-senile dementia, early onset Alzheimer's disease, senile dementia, dementia of the Alzheimer's type, Lewy body dementia, vascular dementia, Alzheimer's disease, stroke, AIDS dementia complex, attention deficit disorder, attention deficit hyperactivity disorder, dyslexia, schizophrenia, schizophreniform disorder, or schizoaffective disorder.
  • Another aspect of the present invention includes use of a compound of the present invention in the manufacture of a medicament for the treatment or prevention of pain.
  • Another aspect of the present invention includes a method of treating or preventing pain comprising administering a compound or pharmaceutical composition of the present invention.
  • One embodiment of the compound, use, or method aspects of the present invention includes therapy of acute pain, persistent pain, chronic pain, nociceptive pain, neuropathic pain, inflammatory pain, fibromyalgia, post-operative pain, pain due to medical condition, arthritis pain, temporomandibular joint disorder, burn pain, injury pain, back pain, sciatica, foot pain, headache, abdominal pain, muscle and connective tissue pain, joint pain, breakthrough pain, cancer pain, somatic pain, visceral pain, chronic fatigue syndrome, psychogenic pain, or pain disorder.
  • neuropathic pain is trigeminal or herpetic neuralgia, diabetic neuropathy, chemotherapy-induced neuropathy, post-herpetic neuralgia, carpel-tunnel syndrome, radiculopathy, complex regional pain syndrome, causalgia, low back pain, spontaneous pain, brachial plexus avulsion, pain resulting from spinal cord injury, hyperalgesia, allodynia, parathesia, or dysthesia.
  • Another aspect of the present invention includes a method of making (2S)- (4E)-N-methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2-amine of high chemical purity (>97%), comprising: reacting (2S)-(4E)-N-methyl-5-[3-(5-methoxypyridin)yl]-4- penten-2-amine with galactaric acid to make (2S)-(4E)-N-methyl-5-[3-(5- methoxypyridin)yl]-4-penten-2-amine hemi-galactarate.
  • Another aspect of the present invention includes a method of making (2S)- (4E)-N-methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2-amine phosphate, comprising: (a) palladium catalyzed coupling of 3-bromo-5-methoxypyridine and a protected (2S)- N-methyl-4-penten-2-amine; (b) removing the protecting group; (c) treatment with galactaric acid to precipitate (2S)-(4E)-N-methyl-5-[3-(5-methoxypyridin)yl]-4-penten- 2-amine hemi-galactarate; (d) converting (2S)-(4E)-N-methyl-5-[3-(5- methoxypyridin)yl]-4-penten-2-amine hemi-galactarate into (2S)-(4E)-N-methyl-5-[3- (5-methoxypyridin)yl]-4-penten-2-amine
  • One embodiment includes wherein the protected (2S)-N-methyl-4-penten-2- amine is (2S)-N-methyl-N-(tert-butoxycarbonyl)-4-penten-2-amine such that the protecting group to be removed is tert-butoxycarbonyl.
  • One aspect of the present invention relates to the hydrochloric acid, sulfuric acid, maleic acid, phosphoric acid, L-glutamic acid, pamoic acid (4,4'- methylenebis(3-hydroxy-2-naphthoic acid), xinafoic acid (1-hydroxy-2-napthoic acid), ketoglutaric acid, L-tartaric acid, fumaric acid, galactaric acid (mucic acid), citric acid, D-glucuronic acid, L-malic acid, hippuric acid (N-benzoylglycine), D-gluconic acid, L- lactic acid, L-aspartic acid, oleic acid (9Z-octadecenoic acid), L-ascorbic acid, benzoic acid, p-hydroxybenzoic acid, succinic acid, adipic acid, acetic acid, propionic acid, stearic acid (octadecanoic acid), malonic acid, lactobionic acid (4-0
  • the present invention includes solid hydrochloric acid, sulfuric acid, maleic acid, phosphoric acid, pamoic acid, xinafoic acid, galactaric acid, L-tartaric acid, hippuric acid, fumaric acid, citric acid, D-glucuronic acid, L-malic acid, D-gluconic acid, L-ascorbic acid, p-hydroxybenzoic acid, stearic acid, lactobionic acid, orotic acid, R-mandelic acid, S-mandelic acid, oxalic acid and hydrobromic acid salts of (2S)-(4E)-N-methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2-amine.
  • the invention also includes the preparation of these salts.
  • the stoichiometric ratio of the acid to the amine base is 1 :1.
  • the stoichiometric ratio of the acid to the amine is 1 :2.
  • the stoichiometric ratio of the acid to the amine is 2:1.
  • the present invention includes crystalline hydrochloric acid, maleic acid, phosphoric acid, pamoic acid, xinafoic acid, fumaric acid, galactaric acid, p- hydroxybenzoic acid, stearic acid, orotic acid, R-mandelic acid, S-mandelic acid, oxalic acid and hydrobromic acid salts of (2S)-(4E)-N-methyl-5-[3-(5- methoxypyridin)yl]-4-penten-2-amine.
  • the salt is (2S)-(4E)-N- methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2-amine phosphate.
  • the salt is (2S)-(4E)-N-methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2- amine hemigalactarate. In yet another embodiment, the salt is (2S)-(4E)-N-methyl-5- [3-(5-methoxypyridin)yl]-4-penten-2-amine stearate. In yet another embodiment, the salt is (2S)-(4E)-N-methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2-amine bis-orotate. In yet another embodiment, the salt is (2S)-(4E)-N-methyl-5-[3-(5-methoxypyridin)yl]- 4-penten-2-amine pamoate.
  • the present invention includes combinations of each of the aspects and embodiments.
  • the present invention includes hydrates and solvates of the salts of the present invention.
  • the present invention includes polymorphic forms of the salts, including hydrates and solvates of the salts, of the present invention. Such polymorphic forms are characterized by their x-ray powder diffraction (XRPD) patterns (diffractograms).
  • XRPD x-ray powder diffraction
  • the polymorph is Form 1 , Form 2, or Form 3 of (2S)-(4E)-N-methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2-amine phosphate.
  • the present invention includes pharmaceutical compositions comprising a salt of the present invention, and hydrates and solvates thereof.
  • the pharmaceutical compositions of the present invention can be used for treating or preventing a wide variety of conditions or disorders, and particularly those disorders characterized by dysfunction of nicotinic cholinergic neurotransmission or the degeneration of the nicotinic cholinergic neurons.
  • the present invention includes a method for treating or preventing disorders and dysfunctions, such as CNS disorders and dysfunctions, and also for treating or preventing certain conditions, for example, alleviating pain and inflammation, in mammals in need of such treatment.
  • the methods involve administering to a subject a therapeutically effective amount of a salt, or hydrate or solvate thereof, of the present invention or a pharmaceutical composition that includes such compounds.
  • the present invention includes a method for the treatment or prevention of pain, inflammation, age-associated memory impairment, mild cognitive impairment, pre-senile dementia, early onset Alzheimer's disease, senile dementia, dementia of the Alzheimer's type, Lewy body dementia, vascular dementia, Alzheimer's disease, stroke, AIDS dementia complex, attention deficit disorder, attention deficit hyperactivity disorder, dyslexia, schizophrenia, schizophreniform disorder, schizoaffective disorder, cognitive deficit in schizophrenia, and cognitive dysfunction in schizophrenia.
  • the present invention includes a method for alleviating pain through administration to a subject in need thereof an effective amount of a composition of the present invention.
  • the type of pain is acute pain, chronic pain, neurologic pain, neuropathic pain, female-specific pain, post-surgical pain, inflammatory pain, or cancer pain.
  • the present invention includes a method of treating chronic or neuropathic pain by administering the compounds of the invention.
  • the compounds are administered to treat chronic or neuropathic pain caused by diabetes or associated with a diabetic state.
  • the compounds are administered to treat chronic or neuropathic pain caused by chemotherapeutic treatment of cancer.
  • Figure 1 shows the XRPD diffractogram of (2S)-(4E)-N-methyl-5-[3-(5- methoxypyridin)yl]-4-penten-2-amine hemi-galactarate.
  • Figure 2 shows the XRPD diffractograms of (2S)-(4E)-N-methyl-5-[3-(5- methoxypyridin)yl]-4-penten-2-amine phosphate salts.
  • Figure 3 shows the XRPD diffractogram of (2S)-(4E)-N-methyl-5-[3-(5- methoxypyridin)yl]-4-penten-2-amine phosphate, Form 1.
  • Figure 4 shows the XRPD diffractogram of (2S)-(4E)-N-methyl-5-[3-(5- methoxypyridin)yl]-4-penten-2-amine maleate.
  • Figure 5 shows the XRPD diffractogram of (2S)-(4E)-N-methyl-5-[3-(5- methoxypyridin)yl]-4-penten-2-amine xinafoate.
  • Figure 6 shows the XRPD diffractograms of (2S)-(4E)-N-methyl-5-[3-(5- methoxypyridin)yl]-4-penten-2-amine hydrochloride salts.
  • Figure 7 shows the XRPD diffractogram of (2S)-(4E)-N-methyl-5-[3-(5- methoxypyridin)yl]-4-penten-2-amine di-orotate.
  • Figure 8 shows the XRPD diffractogram of (2S)-(4E)-N-methyl-5-[3-(5- methoxypyridin)yl]-4-penten-2-amine pamoate salts.
  • Figure 9 show the XRPD diffractogram of (2S)-(4E)-N-methyl-5-[3-(5- methoxypyridin)yl]-4-penten-2-amine fumarate.
  • Figure 10 shows the XRPD diffractogram of (2S)-(4E)-N-methyl-5-[3-(5- methoxypyridin)yl]-4-penten-2-amine stearate.
  • Figure 11 shows the XRPD diffractogram of (2S)-(4E)-N-methyl-5-[3-(5- methoxypyridin)yl]-4-penten-2-amine p-hydroxybenzoate.
  • Figure 12 shows the XRPD diffractogram of (2S)-(4E)-N-methyl-5-[3-(5- methoxypyridin)yl]-4-penten-2-amine R-mandelate.
  • FIGS 13 A-E show the XRPD diffractograms of (2S)-(4E)-N- methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2-amine phosphate, Form 1 , from various solvents.
  • Figure 14 shows the XRPD diffractograms of (2S)-(4E)-N-methyl-5-[3-(5- methoxypyridin)yl]-4-penten-2-amine phosphate, Form 2, from various solvents.
  • Figure 15 shows the XRPD diffractograms of (2S)-(4E)-N-methyl-5-[3-(5- methoxypyridin)yl]-4-penten-2-amine phosphate, Form 3, from various solvents.
  • Figure 16 shows the XRPD diffractograms of (2S)-(4E)-N-methyl-5-[3-(5- methoxypyridin)yl]-4-penten-2-amine phosphate, Form 1 , under various temperature and relative humidity (RH) conditions.
  • Figure 17 illustrates gabapentin and vehicle-treated groups tested for allodynia at 6 weeks post-STZ treatment. Gabapentin significantly reversed the allodynia (p ⁇ 0.05).
  • Figure 18 illustrates (2S)-(4E)-N-methyl-5-[3-(5-methoxypyridin)yl]-4-penten- 2-amine, specifically the hemigalatarate, and vehicle-treated groups tested for allodynia at 6 weeks post-STZ treatment.
  • (2S)-(4E)-N-methyl-5-[3-(5- methoxypyridin)yl]-4-penten-2-amine demonstrated a significantly increased allodynia threshold at 2 hr post-dosing (p ⁇ 0.05).
  • Figure 19 illustrates gabapentin and vehicle-treated groups tested for allodynia at baseline, 3 and 4 weeks post-TAXOL administration. Gabapentin significantly reversed the allodynia (p ⁇ 0.001 ).
  • Figure 20 illustrates (2S)-(4E)-N-methyl-5-[3-(5-methoxypyridin)yl]-4-penten- 2-amine and vehicle-treated groups tested for allodynia at baseline, 3 and 4 weeks post-TAXOL administration. Only the high dose of (2S)-(4E)-N-methyl-5-[3-(5- methoxypyridin)yl]-4-penten-2-amine significantly reversed the allodynia (p ⁇ 0.05) at both weeks 3 and 4.
  • White bar indicates vehicle; very lightly shaded bar indicates 0.03 mg/kg (2S)-(4E)-N-methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2-amine; medium shaded bar indicates 0.3 mg/kg (2S)-(4E)-N-methyl-5-[3-(5- methoxypyridin)yl]-4-penten-2-amine; and darkly shaded bar indicates 1 mg/kg (2S)- (4E)-N-methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2-amine
  • the term "compounds” includes salt forms, preferably acid addition salts, of (2S)-(4E)-N-methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2-amine, unless, in that particular context, it is clear that the compound being referred to is the free base itself.
  • the term “compounds” also includes hydrates and solvates of the salt forms.
  • the compounds described herein are salts of (2S)-(4E)-N-methyl-5-[3-(5- methoxypyridin)yl]-4-penten-2-amine, which free base has the formula:
  • (2S)-(4E)-N-methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2-amine and its salts may be prepared in a variety of ways. Approaches for preparing (2S)-(4E)-N-methyl- 5-[3-(5-methoxypyridin)yl]-4-penten-2-amine are described, for example, in U.S. patent No. 7,045,538 to Caldwell et al., herein incorporated by reference.
  • One embodiment of the present invention is a synthesis of (2S)-(4E)-N- methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2-amine that is suitable for use in large scale manufacture.
  • synthetic procedures which can be performed on a multi-kilogram scale, using standard manufacturing equipment, reagents, and protocols.
  • particular synthetic steps vary in their amenability to scale-up. Reactions are found lacking in their ability to be scaled-up for a variety of reasons, including safety concerns, reagent expense, difficult work-up or purification, reaction energetics (thermodynamics or kinetics), and reaction yield.
  • the double bond- containing compound typically includes either a hydroxyl group, which is (subsequent to the Heck reaction) converted to an amine group to form the (2S)-(4E)-N-methyl-5- [3-(5-methoxypyridin)yl]-4-penten-2-amine, or includes a protected amine group, which is de-protected following the Heck reaction to form the (2S)-(4E)-N-methyl-5- [3-(5-methoxypyridin)yl]-4-penten-2-amine.
  • This latter approach is exemplified in the scalable synthesis disclosed herein.
  • a limitation of the Heck coupling chemistry is that, while the major reaction product is the desired E (or trans) isomer, there are minor reaction products, including the Z (or cis) isomer, a coupling product wherein the double bond has migrated from the position adjacent to the pyridine ring to a non-conjugated position, and a coupling product in which the heteroaryl group is attached at the secondary (as opposed to primary) alkene carbon (i.e., a methylene compound).
  • (2S)-(4E)-N-Methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2-amine free base is a viscous oil with limited water solubility.
  • the free base will react with both inorganic and organic acids to make certain acid addition salts that have physical properties, namely crystallinity and water solubility as well as chemical properties, namely stability toward chemical degradation, that are advantageous for the preparation of pharmaceutical compositions.
  • Such salts are reported here.
  • the compounds, namely salt forms, described herein are salt compositions that possess anions derived from hydrochloric acid, sulfuric acid, maleic acid, phosphoric acid, L-glutamic acid, pamoic acid (4,4'-methylenebis(3-hydroxy-2- naphthoic acid), xinafoic acid (1-hydroxy-2-napthoic acid), ketoglutaric acid, L-tartaric acid, fumaric acid, galactaric acid (mucic acid), citric acid, D-glucuronic acid, L-malic acid, hippuric acid (N-benzoylglycine), D-gluconic acid, L-lactic acid, L-aspartic acid, oleic acid (9Z-octadecenoic acid), L-ascorbic acid, benzoic acid, p-hydroxybenzoic acid, succinic acid, adipic acid, acetic acid, propionic acid, stearic acid (octadecanoic acid), malonic acid
  • Phosphoric acid and citric acid each have three acidic protons of varying acid strengths, which can react with one or both of the basic amine groups present on (2S)-(4E)-N-methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2-amine.
  • the acid-base reaction can occur, for example, in a ratio of one phosphoric or citric acid molecule to one, two, or three (2S)-(4E)-N-methyl-5-[3-(5-methoxypyridin)yl]-4- penten-2-amine molecules, two phosphoric or citric acid molecules to one or three (2S)-(4E)-N-methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2-amine molecules, three phosphoric or citric acid molecules to two molecules of (2S)-(4E)-N-methyl-5-[3-(5- methoxypyridin)yl]-4-penten-2-amine. Other ratios are also possible.
  • Galactaric acid and maleic acid each have two acidic protons of varying acid strengths, which can react with one or both of the basic amine groups present on (2S)-(4E)-N-methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2-amine. Accordingly, the acid-base reaction can occur, for example, in a ratio of one galactaric or maleic acid molecule to one or two (2S)-(4E)-N-methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2- amine molecules.
  • two molecules of either galactaric or maleic acid can react with one molecule of (2S)-(4E)-N-methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2- amine.
  • Other ratios are also possible.
  • Orotic acid (uracil-6-carboxylic acid) and R-mandelic acid each have one acidic proton and can combine with (2S)-(4E)-N-methyl-5-[3-(5-methoxypyridin)yl]-4- penten-2-amine in ratios of 2:1 or 1 :1 , acid to base, for instance.
  • the molar ratio of acid to base ((2S)-(4E)-N-methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2-amine) is 1:2 or 1:1 , but other ratios, such as 3:2 and 2:1 , are possible.
  • the salts described herein can have crystal structures that occlude solvents that are present during salt formation.
  • the salts can occur as hydrates and other solvates of varying stoichiometry of solvent relative to the (2S)-(4E)-N-methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2-amine.
  • a further aspect of the present invention comprises processes for the preparation of the salts.
  • the precise conditions under which the salts are formed may be empirically determined.
  • the salts may be obtained by crystallization under controlled conditions.
  • the method for preparing the salt forms can vary.
  • the preparation of (2S)- (4E)-N-methyl-5-[3-(5-methoxypyridin)yl)]-4-penten-2-amine salt forms typically involves:
  • Representative solvents that can be used to prepare or recrystallize the salt forms include, without limitation, ethanol, methanol, isopropyl alcohol, isopropyl acetate, acetone, ethyl acetate, toluene, water, methyl ethyl ketone, and acetonitrile.
  • crystalline salts demonstrated stability sufficient to establish their promise in the production of pharmaceutical preparations. Such stability can be demonstrated in a variety of ways. Propensity to gain and release atmospheric moisture can be assessed by dynamic vapor sorption (DVS), also known as gravimetric vapor sorption (GVS). Stability to elevated temperatures and humidity can be studied by storing the solid salts at 40°C/75%RH for up to eight days, and then re-examining each by weight, appearance under the microscope, and x-ray powder diffraction (XRPD).
  • salts of the invention in forms which are greater than 80% crystalline, by “substantially crystalline” we include greater than 20%, preferably greater than 30%, and more preferably greater than 40% (e.g. greater than any of 50, 60, 70, 80, or 90%) crystalline.
  • the degree (%) of crystallinity may be determined by the skilled person using XRPD. Other techniques, such as solid state NMR, FT-IR, Raman spectroscopy, differential scanning calorimetry (DSC) and microcalorimetry, may also be used.
  • the term "stability" as defined herein includes chemical stability and solid state stability.
  • chemical stability includes the potential to store salts of the invention in an isolated form, or in the form of a formulation in which it is provided in admixture with pharmaceutically acceptable carriers, diluents, or adjuvants, such as in an oral dosage form, such as a tablet, capsule, or the like, under normal storage conditions, with an insignificant degree of chemical degradation or decomposition.
  • solid state stability includes the potential to store salts of the invention in an isolated solid form, or in the form of a solid formulation in which it is provided in admixture with pharmaceutically acceptable carriers, diluents, or adjuvants, such as in an oral dosage form, such as a tablet, capsule, or the like, under normal storage conditions, with an insignificant degree of solid state transformation, such as crystallization, recrystallization, solid state phase transition, hydration, dehydration, salvation, or desolvation.
  • normal storage conditions include one or more of temperatures of between -80 0 C and 50 0 C, preferably between O 0 C and 40°C and more preferably room temperatures, such as 15 0 C to 3O 0 C, pressures of between 0.1 and 2 bars, preferably at atmospheric pressure, relative humidity of between 5 and 95%, preferably 10 to 60%, and exposure to 460 lux of UV/visible light, for prolonged periods, such as greater than or equal to six months.
  • salts of the invention may be found to be less than 15%, more preferably less than 10%, and most preferably less than 5%, chemically degraded or decomposed, or solid state transformed, as appropriate.
  • the present invention includes a method for treating or preventing disorders and dysfunctions, such as CNS disorders and dysfunctions.
  • the present invention includes a method for treating a wide variety of conditions, particularly pain.
  • the present invention also relates to treatment of disorders characterized by dysfunction of nicotinic cholinergic neurotransmission including disorders involving neuromodulation of neurotransmitter release, such as dopamine release.
  • the present invention also relates to methods for treating and preventing disorders, such as CNS disorders, which are characterized by an alteration in normal neurotransmitter release.
  • the methods involve administering to a subject an effective amount of the salt forms, including hydrates and solvates of the salt forms, or pharmaceutical compositions including such salt forms, their hydrates and solvates.
  • One embodiment of the present invention includes a method for the treatment or prevention of CNS disorders and dysfunctions, comprising administering to a mammal in need of such treatment, a therapeutically effective amount of the compound of the present invention.
  • the disorder or dysfunction may be selected from the group consisting of age-associated memory impairment, mild cognitive impairment, pre-senile dementia, early onset Alzheimer's disease, senile dementia, dementia of the Alzheimer's type, Lewy body dementia, vascular dementia, Alzheimer's disease, stroke, AIDS dementia complex, attention deficit disorder, attention deficit hyperactivity disorder, dyslexia, schizophrenia, schizophreniform disorder, schizoaffective disorder, cognitive deficits in schizophrenia, and cognitive dysfunction in schizophrenia.
  • the disorder may be selected from the group consisting of mild to moderate dementia of the Alzheimer's type, attention deficit disorder, attention deficit hyperactivity disorder, mild cognitive impairment, age-associated memory impairment, cognitive deficits in schizophrenia, and cognitive dysfunction in schizophrenia.
  • One embodiment of the present invention includes a method for the treatment or prevention of pain, comprising administering to a mammal in need of such treatment, a therapeutically effective amount of the compound of the present invention.
  • the pain may be selected from the group consisting of acute pain, chronic pain, neurologic pain, neuropathic pain, female-specific pain, post-surgical pain, inflammatory pain, or cancer pain.
  • the present invention includes a pharmaceutical composition
  • a pharmaceutical composition comprising as an active ingredient a therapeutically effective amount of a salt form of (2S)-(4E)-N- methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2-amine, or hydrate or solvate thereof, in association with one or more pharmaceutically acceptable diluents, excipients and/or inert carriers.
  • compositions incorporating a salt form of (2S)- (4E)-N-methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2-amine, when employed in effective amounts, interact with relevant nicotinic receptor sites of a subject, and hence acts as a therapeutic agent to treat and prevent a wide variety of conditions and disorders, particularly pain and those disorders characterized by an alteration in normal neurotransmitter release.
  • the pharmaceutical compositions are believed to be safe and effective with regards to prevention and treatment of a wide variety of conditions and disorders.
  • One embodiment of the present invention includes use of a compound of the present invention in the manufacture of a medicament.
  • One embodiment of the present invention includes a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention and one or more pharmaceutically acceptable carriers.
  • One embodiment of the present invention includes the use of a pharmaceutical composition of the present invention in the manufacture of a medicament for treatment of central nervous system disorders and dysfunctions.
  • Another embodiment of the present invention includes a compound as herein described with reference to any one of the Examples.
  • Another embodiment of the present invention includes a compound of the present invention for use as an active therapeutic substance.
  • Another embodiment of the present invention includes a compound of the present invention for use to modulate an NNR in a subject in need thereof.
  • Another embodiment of the present invention includes a compound of the present invention for use in the treatment or prevention of conditions or disorders mediated by NNRs.
  • Another embodiment of the present invention includes a use of a compound of the present invention in the manufacture of a medicament for use of modulating NNRs in a subject in need thereof.
  • Another embodiment of the present invention includes a use of a compound of the present invention in the manufacture of a medicament for use in the treatment or prevention of conditions or disorders mediated by NNRs.
  • Another embodiment of the present invention includes a method of modulating NNRs in a subject in need thereof through the administration of a compound of the present invention.
  • the scope of the present invention also includes combinations of embodiments.
  • structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structure except for the replacement of a hydrogen atom by a deuterium or tritium, or the replacement of a carbon atom by a 13 C- or 14 C-enriched carbon are within the scope of the invention.
  • the compounds of the present invention may crystallize in more than one form, a characteristic known as polymorphism, and such polymorphic forms (“polymorphs") are within the scope of the present invention.
  • Polymorphism generally can occur as a response to changes in temperature, pressure, or both. Polymorphism can also result from variations in the crystallization process. Polymorphs can be distinguished by various physical characteristics known in the art such as XRPD patterns (diffractograms), solubility in various solvents, and melting point.
  • the present invention includes a salt or solvate of the compounds herein described, including combinations thereof such as a solvate of a salt.
  • the compounds of the present invention may exist in solvated, for example hydrated, as well as unsolvated forms, and the present invention encompasses all such forms.
  • the salts of the present invention are pharmaceutically acceptable salts.
  • pharmaceutically acceptable salts refers to non-toxic salts of the compounds of this invention.
  • the present invention includes specific representative compounds, which are identified herein with particularity.
  • the compounds of this invention may be made by a variety of methods, including well-known standard synthetic methods. Illustrative general synthetic methods are set out below and then specific compounds of the invention are prepared in the working Examples.
  • protecting groups for sensitive or reactive groups are employed where necessary in accordance with general principles of synthetic chemistry.
  • Protecting groups are manipulated according to standard methods of organic synthesis (T. W. Green and P. G. M. Wuts (1991 ) Protecting Groups in Organic Synthesis, John Wiley & Sons, incorporated by reference with regard to protecting groups). These groups are removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art. The selection of processes as well as the reaction conditions and order of their execution shall be consistent with the preparation of compounds of the present invention.
  • the present invention also provides a method for the synthesis of compounds useful as intermediates in the preparation of compounds of the present invention along with methods for their preparation.
  • the compounds can be prepared according to the following methods using readily available starting materials and reagents. In these reactions, variants may be employed which are themselves known to those of ordinary skill in this art, but are not mentioned in greater detail.
  • an "agonist” is a substance that stimulates its binding partner, typically a receptor.
  • Stimulation is defined in the context of the particular assay, or may be apparent in the literature from a discussion herein that makes a comparison to a factor or substance that is accepted as an "agonist” or an “antagonist” of the particular binding partner under substantially similar circumstances as appreciated by those of skill in the art.
  • Stimulation may be defined with respect to an increase in a particular effect or function that is induced by interaction of the agonist or partial agonist with a binding partner and can include allosteric effects.
  • an "antagonist” is a substance that inhibits its binding partner, typically a receptor. Inhibition is defined in the context of the particular assay, or may be apparent in the literature from a discussion herein that makes a comparison to a factor or substance that is accepted as an "agonist” or an “antagonist” of the particular binding partner under substantially similar circumstances as appreciated by those of skill in the art. Inhibition may be defined with respect to a decrease in a particular effect or function that is induced by interaction of the antagonist with a binding partner, and can include allosteric effects.
  • a "partial agonist” or a “partial antagonist” is a substance that provides a level of stimulation or inhibition, respectively, to its binding partner that is not fully or completely agonistic or antagonistic, respectively. It will be recognized that stimulation, and hence, inhibition is defined intrinsically for any substance or category of substances to be defined as agonists, antagonists, or partial agonists.
  • "intrinsic activity” or “efficacy” relates to some measure of biological effectiveness of the binding partner complex. With regard to receptor pharmacology, the context in which intrinsic activity or efficacy should be defined will depend on the context of the binding partner (e.g., receptor/ligand) complex and the consideration of an activity relevant to a particular biological outcome.
  • intrinsic activity may vary depending on the particular second messenger system involved. See Hoyer, D. and Boddeke, H., Trends Pharmacol. Sci. 14(7): 270-5 (1993), herein incorporated by reference with regard to such teaching. Where such contextually specific evaluations are relevant, and how they might be relevant in the context of the present invention, will be apparent to one of ordinary skill in the art.
  • modulation of a receptor includes agonism, partial agonism, antagonism, partial antagonism, or inverse agonism of a receptor.
  • neurotransmitters whose release is mediated by the compounds described herein include, but are not limited to, acetylcholine, dopamine, norepinephrine, serotonin and glutamate, and the compounds described herein function as modulators at the ⁇ 4 ⁇ 2 subtype of the CNS NNRs.
  • prevention or “prophylaxis” include any degree of reducing the progression of or delaying the onset of a disease, disorder, or condition.
  • the term includes providing protective effects against a particular disease, disorder, or condition as well as amelioration of the recurrence of the disease, disorder, or condition.
  • the invention provides a method for treating a subject having or at risk of developing or experiencing a recurrence of a NNR or nAChR mediated disorder.
  • the compounds and pharmaceutical compositions of the invention may be used to achieve a beneficial therapeutic or prophylactic effect, for example, in a subject with a CNS dysfunction.
  • the compounds of the present invention are modulators of the ⁇ 4 ⁇ 2 NNR subtype, characteristic of the CNS, and can be used for preventing or treating various conditions or disorders, including those of the CNS, in subjects which have or are susceptible to such conditions or disorders, by modulation of ⁇ 4 ⁇ 2 NNRs.
  • the compounds have the ability to selectively bind to the ⁇ 4 ⁇ 2 NNRs and express nicotinic pharmacology, for example, to act as agonists, partial agonists, antagonists, as described.
  • compounds of the present invention when administered in effective amounts to patients in need thereof, provide some degree of prevention of the progression of the CNS disorder, namely, providing protective effects, amelioration of the symptoms of the CNS disorder, or amelioration of the reoccurrence of the CNS disorder, or a combination thereof.
  • the compounds of the present invention can be used to treat or prevent those types of conditions and disorders for which other types of nicotinic compounds have been proposed or are shown to be useful as therapeutics. See, for example, the references previously listed hereinabove, as well as Williams et al., Drug News Perspec. 7(4): 205 (1994), Arneric et al., CNS Drug Rev. 1(1): 1-26 (1995), Arneric et al., Exp. Opin. Invest. Drugs 5(1): 79-100 (1996), Bencherif et al., J. Pharmacol. Exp. Ther. 279: 1413 (1996), Lippiello et al., J. Pharmacol. Exp. Ther.
  • the compounds and their pharmaceutical compositions are useful in the treatment or prevention of a variety of CNS disorders, including neurodegenerative disorders, neuropsychiatric disorders, neurologic disorders, and addictions.
  • the compounds and their pharmaceutical compositions can be used to treat or prevent cognitive deficits and dysfunctions, age-related and otherwise; attentional disorders and dementias, including those due to infectious agents or metabolic disturbances; to provide neuroprotection; to treat convulsions and multiple cerebral infarcts; to treat mood disorders, compulsions and addictive behaviors; to provide analgesia; to control inflammation, such as mediated by cytokines and nuclear factor kappa B; to treat inflammatory disorders; to provide pain relief; and to treat infections, as anti- infectious agents for treating bacterial, fungal, and viral infections.
  • diseases and conditions that the compounds and pharmaceutical compositions of the present invention can be used to treat or prevent are: age- associated memory impairment (AAMI), mild cognitive impairment (MCI), age-related cognitive decline (ARCD), pre-senile dementia, early onset Alzheimer's disease, senile dementia, dementia of the Alzheimer's type, Alzheimer's disease, cognitive impairment no dementia (CIND), Lewy body dementia, HIV-dementia, AIDS dementia complex, vascular dementia, Down syndrome, head trauma, traumatic brain injury (TBI), dementia pugilistica, Creutzfeld-Jacob Disease and prion diseases, stroke, ischemia, attention deficit disorder, attention deficit hyperactivity disorder, dyslexia, schizophrenia, schizophreniform disorder, schizoaffective disorder, cognitive dysfunction in schizophrenia, cognitive deficits in schizophrenia, Parkinsonism including Parkinson's disease, postencephalitic parkinsonism, parkinsonism-dementia of Gaum, frontotemporal dementia Parkinson's Type (FTDP), Pick's disease, Niemann
  • Cognitive impairments or dysfunctions may be associated with psychiatric disorders or conditions, such as schizophrenia and other psychotic disorders, including but not limited to psychotic disorder, schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, shared psychotic disorder, and psychotic disorders due to a general medical conditions, dementias and other cognitive disorders, including but not limited to mild cognitive impairment, pre-senile dementia, Alzheimer's disease, senile dementia, dementia of the Alzheimer's type, age-related memory impairment, Lewy body dementia, vascular dementia, AIDS dementia complex, dyslexia, Parkinsonism including Parkinson's disease, cognitive impairment and dementia of Parkinson's Disease, cognitive impairment of multiple sclerosis, cognitive impairment caused by traumatic brain injury, dementias due to other general medical conditions, anxiety disorders, including but not limited to panic disorder without agoraphobia, panic disorder with agoraphobia, agoraphobia without history of panic disorder, specific phobia, social phobia, obsessive-compulsive disorder, post-traumatic stress disorder, acute
  • the above conditions and disorders are discussed in further detail, for example, in the American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision, Washington, DC, American Psychiatric Association, 2000; incorporated herein by reference with regard to defining such conditions and disorders.
  • the compounds of the present invention and their pharmaceutical compositions are particularly useful in treating (providing relief from) and preventing pain, including acute, persistent, and chronic pain.
  • the pain types and painful conditions that can be treated or prevented using the compounds and their pharmaceutical compositions include nociceptive pain, neuropathic pain, inflammatory pain, fibromyalgia, post-operative pain, pain due to medical condition (such as AIDS or other disorder), arthritis pain, temporomandibular joint disorder, burn pain, injury pain, back pain, sciatica, foot pain, headache, abdominal pain, muscle and connective tissue pain, joint pain, breakthrough pain, cancer pain, somatic pain, visceral pain, chronic fatigue syndrome, psychogenic pain, and pain disorder.
  • Neuropathic pain syndromes are the consequence of abnormal changes occurring within pain signaling systems of both the peripheral and central nervous system. Their diverse etiology and symptomatology have traditionally rendered them particularly difficult to treat with any consistency.
  • neuropathic pain syndromes include those attributed to trigeminal or herpetic neuralgia, peripheral neuropathies (diabetic neuropathy, chemotherapy-induced neuropathy), postherpetic neuralgia, entrapment neuropathies (carpel-tunnel syndrome), radiculopathy, complex regional pain syndrome, causalgia, low back pain, spontaneous pain (pain without an external stimulus), and deafferentation syndromes such as brachial plexus avulsion and spinal cord injury.
  • peripheral neuropathies diabetic neuropathy, chemotherapy-induced neuropathy
  • postherpetic neuralgia postherpetic neuralgia
  • entrapment neuropathies carpel-tunnel syndrome
  • radiculopathy complex regional pain syndrome
  • causalgia low back pain
  • spontaneous pain pain without an external stimulus
  • deafferentation syndromes such as brachial plexus avulsion and spinal cord injury.
  • Hyperalgesia strong pain associated with a mild stimulus
  • allodynia pain due associated with an innocuous stimulus
  • parethesias sessari associated with an innocuous stimulus
  • dythesias excaggerated sensations in response to mild stimulus
  • the compounds of the present invention and their pharmaceutical compositions are particularly useful in treating and preventing these neuropathic pain types and associated conditions.
  • the symptoms of neuropathic pain are incredibly heterogeneous.
  • neuropathic pain chronic constriction injury, streptozotocin (STZ)-induced and Paclitaxel (TAXOL)-induced neuropathies
  • STZ streptozotocin
  • TAXOL Paclitaxel
  • the compound (2S)- (4E)-N-methyl-5-(5-methoxy-3-pyridinyl)-4-pentene-2-amine hemigalactarate has demonstrated efficacy in animal neuropathy models, including STZ-induced diabetic neuropathy, and TAXOL-induced neuropathy.
  • the treatment or prevention of diseases, disorders and conditions occurs without appreciable adverse side effects, including, for example, significant increases in blood pressure and heart rate, significant negative effects upon the gastro-intestinal tract, and significant effects upon skeletal muscle.
  • the compounds of the present invention when employed in effective amounts, are believed to modulate the activity of the ⁇ 4 ⁇ 2 NNRs without appreciable interaction with the nicotinic subtypes that characterize the human ganglia, as demonstrated by a lack of the ability to elicit nicotinic function in adrenal chromaffin tissue, or skeletal muscle, further demonstrated by a lack of the ability to elicit nicotinic function in cell preparations expressing muscle-type nicotinic receptors.
  • these compounds are believed capable of treating or preventing diseases, disorders and conditions without eliciting significant side effects associated activity at ganglionic and neuromuscular sites.
  • administering is believed to provide a therapeutic window in which treatment of certain diseases, disorders and conditions is provided, and certain side effects are avoided. That is, an effective dose of the compound is believed sufficient to provide the desired effects upon the disease, disorder or condition, but is believed insufficient, namely is not at a high enough level, to provide undesirable side effects.
  • compositions of the present invention incorporate a compound of the present invention which, when employed in effective amounts, interacts with relevant nicotinic receptor sites of a subject, and acts as a therapeutic agent to treat and prevent a wide variety of conditions and disorders.
  • the pharmaceutical compositions provide therapeutic benefit to individuals suffering from affected disorders or exhibiting clinical manifestations of affected disorders, in that the compounds within those compositions, when employed in effective amounts, are believed to: (i) exhibit nicotinic pharmacology and affect relevant nicotinic receptors sites, for example by acting as a pharmacological agonist to activate a nicotinic receptor; or (ii) elicit neurotransmitter secretion, and hence prevent and suppress the symptoms associated with those diseases; or both.
  • the compounds of the present invention are believed to have the potential to
  • the present invention further provides pharmaceutical compositions that include effective amounts of compounds of the formulae of the present invention and salts and solvates, thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.
  • the compounds of the formulae of the present invention, including salts and solvates, thereof, are as herein described.
  • the carrier(s), diluent(s), or excipient(s) must be acceptable, in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient of the pharmaceutical composition.
  • a process for the preparation of a pharmaceutical formulation including admixing a compound of the formulae of the present invention, including a salt, solvate, or prodrug thereof, with one or more pharmaceutically acceptable carriers, diluents or excipients.
  • compositions are preferably administered orally, for example, in liquid form within a solvent such as an aqueous or non-aqueous liquid, or within a solid carrier.
  • a solvent such as an aqueous or non-aqueous liquid
  • Preferred compositions for oral administration include pills, tablets, capsules, caplets, syrups, and solutions, including hard gelatin capsules and time-release capsules.
  • Compositions may be formulated in unit dose form, or in multiple or subunit doses. Preferred compositions are in liquid or semisolid form.
  • compositions including a liquid pharmaceutically inert carrier such as water or other pharmaceutically compatible liquids or semisolids may be used.
  • a liquid pharmaceutically inert carrier such as water or other pharmaceutically compatible liquids or semisolids.
  • the use of such liquids and semisolids is well known to those of skill in the art.
  • compositions can also be administered via injection, namely, intravenously, intramuscularly, subcutaneously, intraperitoneal ⁇ , intraarterially, intrathecal ⁇ , and intracerebroventricularly.
  • Intravenous administration is a preferred method of injection.
  • Suitable carriers for injection are well known to those of skill in the art, and include 5% dextrose solutions, saline, and phosphate buffered saline.
  • the compounds can also be administered as an infusion or injection, such as, as a suspension or as an emulsion in a pharmaceutically acceptable liquid or mixture of liquids.
  • compositions for transdermal administration may also be administered using other means, for example, rectal administration.
  • Formulations useful for rectal administration such as suppositories, are well known to those of skill in the art.
  • the compounds can also be administered by inhalation, including, in the form of an aerosol either nasally or using delivery articles of the type set forth in U.S. Patent No. 4,922,901 to Brooks et al., the disclosure of which is incorporated herein; topically, such as, in lotion form; transdermal ⁇ , such as, using a transdermal patch, using technology that is commercially available from Novartis and Alza Corporation; by powder injection; or by buccal, sublingual, or intranasal absorption.
  • a compositions for transdermal administration includes the active ingredient in conjunction with carriers and excipients, such as permeation enhancers, which promote transdermal absorption of the active ingredient after transdermal administration.
  • the amount of active ingredient absorbed depends on many factors. These factors include the active ingredient concentration, the active ingredient delivery vehicle, the skin contact time, the area of the skin dosed, the ratio of the ionized and unionized forms of the active ingredient at the pH of the absorption site, the molecular size of the active ingredient molecule, and the active ingredient's relative lipid solubility.
  • a transdermal device for delivering the active ingredients described herein can be of any type known in the art, including the monolithic, matrix, membrane, and other types typically useful for administering active ingredients by the transdermal route.
  • Such devices are disclosed in U.S. Pat. Nos. 3,996,934; 3,797,494; 3,742,951 ; 3,598,122; 3,598,123; 3,731,683; 3,734,097; 4,336,243; 4,379,454; 4,460,372; 4,486,193; 4,666,441 ; 4,615,699; 4,681 ,584; and 4,558,580 among others; the disclosures of which are incorporated herein by reference.
  • the active ingredient, or pharmaceutically acceptable salt thereof is typically present in a solution or dispersion, which can be in the form of a gel, a solution, or a semi-solid, and which aids in active ingredient delivery through the stratum corneum of the epidermis and to the dermis for absorption.
  • a solution or dispersion which can be in the form of a gel, a solution, or a semi-solid, and which aids in active ingredient delivery through the stratum corneum of the epidermis and to the dermis for absorption.
  • Membrane devices typically have four layers: (1) an impermeable backing, (2) a reservoir layer, (3) a membrane layer (which can be a dense polymer membrane or a microporous membrane), and (4) a contact adhesive layer which either covers the entire device surface in a continuous or discontinuous coating or surrounds the membrane layer.
  • Examples of materials that may be used to act as an impermeable layer are high, medium, and low density polyethylene, polypropylene, polyvinylchloride, polyvinylidene chloride, polycarbonate, polyethylene terepthalate, and polymers laminated or coated with aluminum foil. Others are disclosed in the standard transdermal device patents mentioned herein.
  • the outer edge of the backing layer can overlay the edge of the reservoir layer and be sealed by adhesion or fusion to the diffusion membrane layer. In such instances, the reservoir layer need not have exposed surfaces.
  • the reservoir layer is underneath the impermeable backing and contains a carrier liquid, typically water and/or an alcohol, or polyol or ester thereof, and may or may not contain the active ingredients.
  • the reservoir layer can include diluents, stabilizers, vehicles, gelling agents, and the like in addition to the carrier liquid and active ingredients.
  • the diffusion membrane layer of the laminate device can be made of a dense or microporous polymer film that has the requisite permeability to the active ingredient and the carrier liquid.
  • the membrane is impermeable to ingredients other than the active ingredient and the carrier liquid, although when buffering at the skin surface is desired, the membrane should be permeable to the buffer in the composition as well.
  • Examples of polymer film that may be used to make the membrane layer are disclosed in U.S. Pat. Nos. 3,797,454 and 4,031 ,894, each herein incorporated by reference.
  • the preferred materials are polyurethane, ethylene vinyl alcohol polymers, and ethylene/vinyl acetate.
  • a membrane layer (which can be a dense polymer membrane or a microporous membrane), and
  • a contact adhesive layer which either covers the entire device surface in a continuous or discontinuous coating or surrounds the membrane layer.
  • composition above comprised in the reservoir the active ingredient in phosphate buffered saline solution.
  • the hydroxybenzoate salt of the active ingredient is used in the composition above.
  • the active ingredient in the reservoir of the composition above is present in a concentration of from 30 to 200 mg per gram of saline solution.
  • the concentration of the active ingredient in the reservoir of the composition above is 35 or 135 mg per gram of saline solution.
  • the second class of transdermal systems is represented by monolithic matrices.
  • monolithic devices are U.S. Pat. No. 4,291 ,014, U.S. Pat. No. 4,297,995, U.S. Pat. No. 4,390,520, and U.S. Pat. No. 4,340,043, each herein incorporated by reference. Others are known to those of ordinary skill in this art.
  • Monolithic and matrix type barrier transdermal devices typically include: (1) Porous polymers or open-cell foam polymers, such as polyvinyl chloride
  • Gels of liquids typically including water and/or hydroxyl-containing solvents such as ethanol, and often containing gelling agents such PVP, carboxymethylcellulose (CMC), hydroxypropylcellulose such as sold undere the tradename Klucel®, HPMC, alginates, kaolinate, bentonite, or montmorillonite, other clay fillers, stearates, silicon dioxide particles, and the like;
  • gelling agents such PVP, carboxymethylcellulose (CMC), hydroxypropylcellulose such as sold undere the tradename Klucel®, HPMC, alginates, kaolinate, bentonite, or montmorillonite, other clay fillers, stearates, silicon dioxide particles, and the like;
  • Nonwoven materials made of textiles, celluloses, polyurethanes, polyester, or other fiber;
  • Sponges which can be formed from natural or foamed polymers; and (6) Adhesives, ideally dermatologically-acceptable pressure sensitive adhesives, for example, silicone adhesives or acrylic adhesives.
  • polymeric barrier materials include, but are not limited to:
  • Polycarbonates such as those formed by phosgenation of a dihydroxy aromatic such as bisphenol A, including materials are sold under the trade designation Lexan® (the General Electric Company);
  • Polyvinylchlorides such as Geon® 121 (B. G. Goodrich Chemical Company); Polyamides (“nylons”), such as polyhexamethylene adipamide, including
  • Modacry ⁇ c copolymers such as DYNEL®, are formed of polyvinylchloride (60 percent) and acrylonitrile (40 percent), styrene-acrylic acid copolymers, and the like.
  • Polysulfones for example, those containing diphenylene sulfone groups, for example, P-1700 (Union Carbide Corporation).
  • Halogenated polymers for example, polyvinylidene fluoride, such as Kynar®
  • Polychlorethers for example, Penton® (Hercules Incorporated), and other thermoplastic polyethers.
  • Acetal polymers for example, polyformaldehydes, such as Delrin® (E. I. DuPont de Nemours & Co.).
  • Acrylic resins for example, polyacrylonitrile, polymethyl methacrylate (PMMA), poly n-butyl methacrylate, and the like.
  • Other polymers such as polyurethanes, polyimides, polybenzimidazoles, polyvinyl acetate, aromatic and aliphatic, polyethers, cellulose esters, e.g., cellulose triacetate; cellulose; colledion (cellulose nitrate with 11% nitrogen); epoxy resins; olefins, e.g., polyethylene, polypropylene; polyvinylidene chloride; porous rubber; cross linked poly(ethylene oxide); cross-linked polyvinylpyrrolidone; cross-linked polyvinyl alcohol); polyelectrolyte structures formed of two ionically associated polymers of the type as set forth in U.S.
  • the thickness of the membrane or barrier can be reduced. However, the thickness should not be reduced to the point where it is likely to tear, or to a point where the amount of active ingredient which can be administered is too low.
  • the transdermal drug delivery compositions typically include a contact adhesive layer to adhere the device to the skin.
  • the active agent may, in some embodiments, reside in the adhesive.
  • Exemplary adhesives include polyurethanes; acrylic or methacrylic resins such as polymers of esters of acrylic or methacrylic acid with alcohols such as n- butanol, n-pentanol, isopentanol, 2-methylbutanol, 1-methylbutanol, 1- methylpentanol, 2-methylpentanol, 3-methylpentanol, 2-ethylbutanol, isooctanol, n- decanol, or n-dodecanol, alone or copolymerized with ethylenically unsaturated monomers such as acrylic acid, methacrylic acid, acrylamide, methacrylamide, N- alkoxymethyl acrylamides, N-alkoxymethyl methacrylamides, N-tertbutylacrylamide
  • silicone adhesives include silicone elastomers based on monomers of silanes, halosilanes, or Ci -I8 alkoxysilanes, especially polydimethylsiloxanes which may be used alone or formulated with a silicone tackifier or silicone plasticizer which are selected from medically acceptable silicone fluids, i.e. non-elastomeric silicones based on silanes, halosilanes or C 1-18 alkoxysilanes.
  • Typical silicone adhesives are available from Dow Corning under the tradename SILASTIC®.
  • Liquid Vehicles Transdermal compositions can include a variety of components, including a liquid vehicle, typically a C 2-4 alkanol such as ethanol, isopropanol, n-propanol, butanol, a polyalcohol or glycol such as propylene glycol, butylene glycol, hexylene glycol, ethylene glycol, and/or purified water.
  • a liquid vehicle typically a C 2-4 alkanol such as ethanol, isopropanol, n-propanol, butanol, a polyalcohol or glycol such as propylene glycol, butylene glycol, hexylene glycol, ethylene glycol, and/or purified water.
  • the vehicle is typically present in an amount of between about 5 and about 75% w/w, more typically, between about 15.0% and about 65.0% w/w, and, preferably, between about 20.0 and 55.0% w/w
  • Water augments the solubility of hydrophilic active agents in the composition, and accelerates the release of lipophilic active agents from a composition.
  • Alcohols such as ethanol, increase the stratum corneum liquid fluidity or function to extract lipids from the stratum corneum.
  • the glycols can also act as permeation enhancers.
  • Permeation Enhancers Successful transdermal delivery depends among others on sufficient flux of the active ingredient across skin, and sufficient surface area of skin, to produce an efficacious plasma concentration of the active ingredient. For reasons of consumer acceptance, the practical surface area of a transdermal system is limited from approximately 4 to 100 cm 2 . With this limitation on surface area, the therapeutic transdermal administration of many active ingredients requires an increase in the inherent skin permeability to obtain the necessary flux. Accordingly, active ingredients have been developed which enhance percutaneous absorption of the active ingredients to be administered. Permeation enhancers are described, for example, in U.S. Patent Nos.
  • the permeation enhancers should both enhance the permeability of the stratum corneum, and be non-toxic, non-irritant and non-sensitizing on repeated exposure.
  • Representative permeation enhancers include, for example, sucrose monococoate, glycerol monooleate, sucrose monolaurate, glycerol monolaureate, diethylene glycol monoalkyl ethers such as diethylene glycol monoethyl or monomethyl ether (Transcutol® P), ester components such as propylene glycol monolaurate, methyl laurate, and lauryl acetate, monoglycerides such as glycerol monolaurate, fatty alcohols such as lauryl alcohol, and 2-ethyl-1 ,3 hexanediol alone or in combination with oleic acid.
  • the transdermal compositions are provided with skin permeation enhancing benefits by combining the active ingredients with saturated fatty alcohols, or forming salts of the active ingredients with one or more fatty acids, such as those of the formula CH 3 -(CH 2 ) H -CH 2 OH or CH 3 -(CH 2 )n-CH 2 COOH respectively, in which n is an integer from 8 to 22, preferably 8 to 12, most preferably 10, or an unsaturated fatty alcohol or fatty acid given by the formula CH 3 -(C n H 2(H-X) )- OH or CH 3 -(C n H 2(H - Xj )-COOH respectively in which n is an integer from 8 to 22 and x is the number of double bonds; and preferably also a second component that is a monoalkyl ether of diethylene glycol, preferably diethylene glycol monoethyl ether or diethylene glycol monomethyl ether, in a vehicle or carrier composition, integrated by an C 1-4 alkano
  • a binary system including a combination of oleic acid or oleic alcohol and a lower alcohol, or a combination of a lower alkyl ester of a polycarboxylic acid, an aliphatic monohydroxy alcohol and an aliphatic diol, can be used.
  • Representative permeation enhancers include fatty alcohols and fatty acids, and monoalkyl ethers of diethylene glycol such as diethylene glycol monoethyl ether or diethylene glycol monomethyl ether.
  • the fatty alcohols are typically present in an amount of between about 0.1 and about 20.0% w/w, preferably between about 0.2 and about 10.0% w/w, and more preferably, between about 0.4 and about 3.0% w/w.
  • the diethylene glycol monoalkyl ethers are typically present in an amount up to 40.0% w/w, preferably between about 0.2 and 25.0% w/w, and, more preferably, between about 2.0 and about 8.0% w/w.
  • the diethylene glycol monoalkyl ethers dissolve both hydrophilic and a lipophilic active agents therein, and facilitates the penetration of the active agents to the skin.
  • Glycols such as propylene glycol, act as a cosolvent of the active agents, and thus increase their solubility in the composition. Further, they tend to solvate the intracellular keratin of the stratum corneum, and thus enhance drug mobility and skin hydration.
  • Gelling agents such as carbomer, carboxyethylene or polyacrylic acid such as Carbopol® 980 or 940 NF, 981 or 941 NF, 1382 or 1342 NF, 5984 or 934 NF, ETD 2020, 2050, 934P NF, 971 P NF, 974P NF, Noveon® AA-1 USP, etc; cellulose derivatives such as ethylcellulose, hydroxypropylmethylcellulose (HPMC), ethylhydroxyethylcellulose (EHEC), carboxymethylcellulose (CMC), hydroxypropylcellulose (HPC) (Klucel®, different grades), hydroxyethylcellulose (HEC) (Natrosol® grades), HPMCP 55, Methocel® grades, etc; natural gums such as arabic, xanthan, guar gums, alginates, etc; polyvinylpyrrolidone derivatives such as Kollidon® grades; polyoxyethylene polyoxypropylene copolymers such as
  • Representative gelling agents include, but are not limited to, Carbopol® 980 NF, Lutrol® F 127, Lutrol® F 68 and Noveon® AA- 1 USP.
  • the gelling agent is present from about 0.2 to about 30.0% w/w, depending on the type of polymer. Preservatives
  • the transdermal compositions can also include one or more preservatives and/or antioxidants.
  • Representative preservatives include quaternary ammonium salts such as lauralkonium chloride, benzalkonium chloride, benzododecinium chloride, cetyl pyridium chloride, cetrimide, domiphen bromide; alcohols such as benzyl alcohol, chlorobutanol, o-cresol, phenylethyl alcohol; organic acids or salts thereof such as benzoic acid, sodium benzoate, potassium sorbate, parabens; or complex forming agents such as ethylenediaminetetraacetic acid (EDTA).
  • Representative antioxidants include butylhydroxytoluene, butylhydroxyanisole, ethylenediaminetetraacetic acid and its sodium salts, D,L-alpha tocoferol.
  • Other Components include butylhydroxytoluene, butylhydroxyanisole, ethylenediaminetetra
  • diluents such as cellulose, microcrystalline cellulose, hydroxypropyl cellulose, starch, hydroxypropylmethyl cellulose and the like. Excipients can be added to adjust the tonicity of the composition, such as sodium chloride, glucose, dextrose, mannitol, sorbitol, lactose and the like. Acidic or basic buffers can also be added to control the pH. Co-solvents or solubilizers such as glycerol, polyethylene glycols, polyethylene glycols derivatives, polyethylene glycol 660 hydroxystearate (Solutol HS15 from BASF), butylene glycol, hexylene glycol, and the like, can also be added.
  • the administration of the active agent can be controlled by using controlled release compositions, which can provide rapid or sustained release, or both, depending on the compositions.
  • particulate drug delivery vehicles known to those of skill in the art which can include the active ingredients, and deliver them in a controlled manner.
  • examples include particulate polymeric drug delivery vehicles, for example, biodegradable polymers, and particles formed of non-polymeric components. These particulate drug delivery vehicles can be in the form of powders, microparticles, nanoparticles, microcapsules, liposomes, and the like.
  • the active agent is in particulate form without added components, its release rate depends on the release of the active agent itself.
  • the active agent is in particulate form as a blend of the active agent and a polymer, the release of the active agent is controlled, at least in part, by the removal of the polymer, typically by dissolution or biodegradation.
  • the compositions can provide an initial rapid release of the active ingredient followed by a sustained release of the active ingredient.
  • U.S. Patent No. 5,629,011 provides examples of this type of composition and is incorporated herein by reference in its entirety.
  • transdermal compositions that use transdermal delivery to deliver nicotine in a time-release manner (such as rate-controlling membranes), including currently marketed nicotine replacement therapies. These are also suitable for administering the active compounds herein described.
  • the transdermal dosage form is not a "patch," but rather, a semisolid dosage form such as a gel, cream, ointment, liquid, etc.
  • a semisolid dosage form such as a gel, cream, ointment, liquid, etc.
  • the dosage form can include other active and inactive components typically seen in semisolid dosage forms used to treat pain.
  • active and inactive components typically seen in semisolid dosage forms used to treat pain.
  • these include, but are not limited to, menthol, wintergreen, capsaicin, aspirin, NSAIDs, narcotic agents (e.g. fentanyl), alcohols, oils such as emu oil, and solvents such as DMSO.
  • the active ingredients can also be delivered via iontophoresis.
  • Iontophoresis is a non-invasive method of propelling high concentrations of a charged substance, such as the active ingredients described herein, transdermal ⁇ by repulsive electromotive force.
  • the technique involves using a small electrical charge applied to an iontophoretic chamber containing a similarly charged active agent and its vehicle. The skin's permeability is altered upon application of the charge, and this increases migration of the active ingredient into the epidermis.
  • one or two chambers are filled with a solution containing one or more of the active agents and a solvent (the "vehicle").
  • the positively charged chamber (“the anode”) will repel a positively charged chemical into the skin.
  • the negatively charged chamber (“the cathode”), will repel a negatively charged chemical into the skin.
  • the active ingredients are cationic, they are administered iontophoretically via the anode.
  • Iontophoresis can be used to transdermal ⁇ deliver the active agents, using active transportation within an electric field, typically by electromigration and electroosmosis. These movements are typically measured in units of chemical flux, commonly ⁇ mol/cm 2 *h.
  • the isoelectric point of the skin is approximately 4. Under physiological conditions, where the surface of the skin is buffered at or near 7.4, the membrane has a net negative charge, and electroosmotic flow is from anode (-) to cathode (+). Electroosmosis augments the anodic delivery of the (positively charged) active agents described herein.
  • iontophoretic transport There are a number of factors that influence iontophoretic transport, including skin pH, the concentration and characteristics of the active agent, ionic competition, molecular size, current, voltage, time applied and skin resistance.
  • the current density of the treatment electrode is perhaps the most important variable, relative to the degree of ion transfer. Comparable iontophoretic doses delivered at low currents over longer periods are more effective than those delivered by high currents over short periods.
  • Iontophoresis devices include two electrodes, which are typically attached to a patient, each connected via a wire to a microprocessor controlled electrical instrument.
  • the active agents are placed under one or both of the electrodes, and are delivered into the body as the instrument is activated.
  • the instrument is typically designed to regulate both current flow and application time. Examples of such instruments are described in U.S. Patent Nos. 5,254,081, and 5,431,625, the contents of which are hereby incorporated by reference.
  • Power for these devices is usually provided by DC batteries, which when providing power for the microprocessor controlled circuitry allow application of a voltage to the electrodes to create a regulated current flow.
  • ions are delivered into the body from an aqueous drug reservoir contained in the iontophoretic device, and counter ions of opposite charge are delivered from a "counter reservoir.”
  • Solutions containing the active ingredient, and also solutions of the counter ions, can be stored remotely and introduced to an absorbent layer of the iontophoresis electrode at the time of use. Examples of such systems are described in U.S. Pat. Nos. 5,087,241 ; 5,087,242; 5,846,217; and 6,421,561, the contents of which are hereby incorporated by reference.
  • the active agents can be pre-packaged in dry form into the electrode(s). This approach requires a moisture activation step at the time of use.
  • Solutions of the active agents can be co-packaged with the iontophoretic device, ideally positioned apart from the electrodes and other metallic components until the time of use.
  • This technique, and suitable devices are described, for example, in U.S. Patent Nos. 5,158,537; 5,288,289; 5,310,404; 5,320,598; 5,385,543; 5,645,527; 5,730,716; and 6,223,075, each of which is incorporated by reference.
  • a co-packaged electrolyte constituent liquid is stored remotely from the electrodes, in a rupturable container and a mechanical action step at the time of use induces a fluid transfer to a receiving reservoir adjacent to the electrodes.
  • the active agents can be present in a pre-formed gel, as described in U.S. Patent No. 4,383,529, incorporated by reference.
  • a preformed gel containing the active agent can be transferred into an electrode receptacle at the time of use.
  • This system can be advantageous in that it provides a precise pre-determined volume of the gel, thus preventing over-filling.
  • the active agent since the active agent is present in a gel composition, it is less likely to leak during storage or transfer.
  • each compound in the form of a pharmaceutical composition or formulation for efficient and effective administration.
  • compositions can be administered in the form of a tablet, a hard gelatin capsule or as a time release capsule.
  • These formulations may contain a liquid carrier that may be oily, aqueous, emulsified or contain certain solvents suitable to the mode of administration.
  • the administration of the pharmaceutical compositions described herein can be intermittent, or at a gradual, continuous, constant or controlled rate to a warmblooded animal, for example, a mammal such as a mouse, rat, cat, rabbit, dog, pig, cow, or monkey; but advantageously is administered to a human being.
  • a warmblooded animal for example, a mammal such as a mouse, rat, cat, rabbit, dog, pig, cow, or monkey
  • the time of day and the number of times per day that the pharmaceutical composition is administered can vary.
  • an effective amount of compound is an amount sufficient to pass across the blood-brain barrier of the subject, to bind to relevant receptor sites in the brain of the subject, and to modulate the activity of relevant nicotinic receptor subtypes, namely modulate neurotransmitter secretion, thus resulting in effective prevention or treatment of the disorder.
  • prevention of the disorder may be manifested by delaying the onset of the symptoms of the disorder and treatment of the disorder may be manifested by a decrease in the symptoms associated with the disorder or an amelioration of the reoccurrence of the symptoms of the disorder.
  • the effective dose can vary, depending upon factors such as the condition of the patient, the severity of the symptoms of the disorder, and the manner in which the pharmaceutical composition is administered.
  • the effective dose of typical compounds generally requires administering the compound in an amount sufficient to modulate disease-relevant receptors to affect neurotransmitter (e.g., dopamine) release but the amount should be insufficient to induce effects on skeletal muscles and ganglia to any significant degree.
  • the effective dose of compounds will of course differ from patient to patient but in general includes amounts starting where CNS effects or other desired therapeutic effects occur, but below the amount where muscular and ganglionic effects are observed.
  • compounds require administering in an amount of less than 5 mg/kg of patient weight.
  • the compounds may be administered in an amount from less than about 1 mg/kg patient weight to less than about 100 ⁇ g/kg of patient weight, and occasionally between about 10 ⁇ g/kg to less than 100 ⁇ g/kg of patient weight.
  • the foregoing effective doses typically represent that amount administered as a single dose, or as one or more doses administered over a 24 hours period.
  • the effective dose of the compounds may require administering the compound in an amount of at least about 1 , but not more than about 1000, and often not more than about 500 mg/ 24 hr/ patient.
  • the present invention also encompasses combination therapy for treating or preventing a disorder mediated by a NNR or nAChR in a subject.
  • the combination therapy comprises administering to the subject a therapeutically or prophylactically effective amount of a compound of the present invention and one or more other therapy including chemotherapy, radiation therapy, gene therapy, or immunotherapy.
  • the compounds of the present invention may be administered in combination with other therapeutic compounds.
  • a compound of this invention can be used in combination with other NNR ligands (such as varenicline), antioxidants (such as free radical scavenging agents), antibacterial agents (such as penicillin antibiotics), antiviral agents (such as nucleoside analogs, like zidovudine and acyclovir), anticoagulants (such as warfarin), anti-inflammatory agents (such as NSAIDs), anti-pyretics, analgesics, anesthetics (such as used in surgery), acetylcholinesterase inhibitors (such as donepezil and galantamine), antipsychotics (such as haloperidol, clozapine, olanzapine, and quetiapine), immuno-suppressants (such as cyclosporin and methotrexate), neuroprotective agents, steroids (such as steroid hormones
  • the compounds of the present invention may be administered in combination with other compounds known to provide relief from pain.
  • Such compounds include opioids (such as morphine), NSAIDs (such as aspirin or ibuprofen), and anticonvulsants (such as gabapentin and pregabalin).
  • opioids such as morphine
  • NSAIDs such as aspirin or ibuprofen
  • anticonvulsants such as gabapentin and pregabalin.
  • the compounds of the present invention may be employed alone or in combination with other therapeutic agents, including other compounds of the present invention.
  • Such a combination of pharmaceutically active agents may be administered together or separately and, when administered separately, administration may occur simultaneously or sequentially, in any order. The amounts of the compounds or agents and the relative timings of administration will be selected in order to achieve the desired therapeutic effect.
  • the administration in combination of a compound of the formulae of the present invention including salts or solvates thereof with other treatment agents may be in combination by administration concomitantly in: (1) a unitary pharmaceutical composition including both compounds; or (2) separate pharmaceutical compositions each including one of the compounds.
  • the combination may be administered separately in a sequential manner wherein one treatment agent is administered first and the other second or vice versa. Such sequential administration may be close in time or remote in time.
  • the compounds of the present invention may be used in the treatment of a variety of disorders and conditions and, as such, the compounds of the present invention may be used in combination with a variety of other suitable therapeutic agents useful in the treatment or prophylaxis of those disorders or conditions.
  • (2S)-(4E)-N-Methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2-amine hemi- galactarate can be produced according to the following techniques.
  • a 20-L glass reaction flask was equipped with a mechanical stirrer, temperature probe and condenser, and the flask was placed under as inert atmosphere.
  • 3-Bromo-5-methoxypyridine (1.50 kg, 8.00 mol) and (3.45 kg) of toluene were added to the flask.
  • palladium(ll) acetate (19.2 g, 0.0855 mol)
  • triphenylphosphine (44.7 g, 0.170 mol)
  • potassium carbonate (1.40, 10.1 mol)
  • (2S)-N-methyl-N-(tert-butoxycarbonyl)-4-penten-2-amine (1.68 kg, factored for purity, 8.43 mol) was added.
  • the temperature of the reaction was gradually increased (in 10°C increments) to 110 0 C ⁇ 5 0 C.
  • the reaction was stirred for 16 h, maintaining the temperature at 115 0 C ⁇ 5°C, at which time the reaction appeared to be complete by thin layer chromatographic analysis.
  • the contents of the B ⁇ chner flask were transferred to a clean, dry 20-L glass reaction flask equipped with a mechanical stirrer, temperature probe, condenser, and under an inert atmosphere.
  • the temperature of the mixture was increased to 40°C ⁇ 5°C and maintained at that temperature as thiol-functionalized silica gel (540 g) was added.
  • the resulting mixture was stirred for 6 h and filtered through a cake of diatomaceous earth (250 g) in a B ⁇ chner funnel into a 20-L B ⁇ chner flask.
  • the reaction vessel and the filter cake were rinsed with ethyl acetate (1.0 L), and the filter cake was washed with an additional portion (1.0 kg) of ethyl acetate.
  • the contents of the B ⁇ chner flask were transferred to a dry rotary evaporator flask and concentrated to constant volume, using a bath temperature of 40 0 C ⁇ 5°C.
  • the residue was dissolved in toluene (2.00 kg) in the rotary evaporator flask, and the mixture was concentrated to constant volume, again using a bath temperature of 40 0 C ⁇ 5°C.
  • the contents of the rotary evaporator flask were dissolved in methanol (790 g), by rotation of the flask for about 0.5 h, and transferred to a 20-L glass reaction flask equipped with a mechanical stirrer, temperature probe, condenser and inert atmosphere. As this solution was stirred and cooled in an ice bath, it was treated with a solution made by combining concentrated aqueous hydrochloric acid (2.0 kg) and water (2.0 L). This addition took about 2 h. The ice bath was then removed, and the contents of the reaction flask were stirred for 5 h at 24°C ⁇ 4 0 C, at which time thin layer chromatographic analysis indicated that the reaction was complete.
  • the contents of the reaction flask were transferred to a clean, dry 20-L rotary evaporator flask and concentrated at 35 0 C ⁇ 5°C.
  • the remaining aqueous solution was transferred to a 20-L glass reaction flask, equipped with a mechanical stirrer, temperature probe, condenser and inert atmosphere.
  • the solution was washed twice with portions of dichloromethane (1.0 L each) by adding the dichloromethane, stirring for about 10 min, separating the layers, and discarding the dichloromethane layer.
  • Dichloromethane (5.0 L) was again added to the aqueous layer, and the stirred mixture was cooled (initially to ⁇ 10°C and maintained at ⁇ 15°C) as aqueous sodium hydroxide solution (made by dissolving 2.0 kg of sodium hydroxide in 15.0 L of water), sufficient to adjust the pH to 13 ⁇ 0.5, was added.
  • the reaction mixture was stirred for an additional 10 min, and the organic layer was separated and placed in a clean, dry 20-L reaction flask.
  • the aqueous layer was extracted with an additional portion of dichloromethane (5.0 L), and the two organic layers were combined and washed with saturated aqueous sodium chloride solution (2.0 L) by stirring the mixture for about 10 min.
  • the reaction mixture was heated at 8O 0 C ⁇ 10 0 C for about 30 min and filtered under vacuum into a 20-L B ⁇ chner flask.
  • the hot contents of the B ⁇ chner flask were transferred into a clean, dry 20-L glass reaction flask and were stirred as the flask was allowed to cool to ambient temperature (25°C ⁇ 2 0 C). Further cooling of the slurry to 5 0 C ⁇ 2 0 C for 5 h, followed vacuum filtration of the slurry through a B ⁇ chner funnel into a 20-L B ⁇ chner flask, provided the crude salt.
  • Cold 2-propanol (2.0 L) was used to rinse the flask with and wash the filter cake.
  • the salt was recrystallized in a 20-L glass reaction flask, equipped with a mechanical stirrer and inert atmosphere, using 2-propanol (6.58 L) and water (484 mL). The mixture was stirred and heated to about 80 0 C, and this temperature was maintained for about 30 minutes, to obtain a clear solution. The hot solution was filtered under vacuum into a 20-L B ⁇ chner flask, and the still hot filtrate was transferred into a clean, dry 20-L flask. The contents of the flask were stirred as the flask was cooled to ambient temperature (25 0 C ⁇ 2 0 C).
  • the slurry was further cooled at 5 0 C ⁇ 2°C for 5 h and vacuum filtered through a B ⁇ chner funnel into a 20-L B ⁇ chner flask.
  • the flask and filter cake were rinsed with cold 2-propanol (2.0 L).
  • the filter cake was rinsed with an additional portion of 2-propanol (2.0 L).
  • X-Ray Powder Diffraction patterns were collected on a Bruker AXS C2 GADDS diffractometer using CuKa radiation (4OkV, 4OmA), automated XYZ stage, laser video microscope for auto-sample positioning and a HiStar 2-dimensional area detector.
  • X-ray optics consists of a single G ⁇ bel multilayer mirror coupled with a pinhole collimator of 0.3mm.
  • the beam divergence i.e. the effective size of the X- ray beam on the sample
  • a ⁇ - ⁇ continuous scan mode was employed with a sample - detector distance of 20 cm which gives an effective 2 ⁇ range of 3.2° - 30.0°. Typically the sample would be exposed to the X-ray beam for 120 seconds.
  • Samples run under ambient conditions were prepared as flat plate specimens using powder as received without grinding. Approximately 1-2 mg of the sample was lightly pressed on a silicon wafer to obtain a flat surface. Samples run under non-ambient conditions were mounted on a silicon wafer with heat-conducting compound. The sample was then heated to the appropriate temperature at ca. 10°C/min and subsequently held isothermally for about 5 min before data collection was initiated.
  • DSC data were collected on a TA Instruments Q1000 equipped with a 50 position auto-sampler. The instrument was calibrated for energy and temperature calibration using certified indium. Typically 0.5-1.5 mg of each sample, in a pin- holed aluminum pan, was heated at 10°C/min from 25 0 C to 175-200 0 C. A nitrogen purge at 30 ml_/min was maintained over the sample.
  • TGA Thermo-Gravimetric Analysis
  • TGA data were collected on a TA Instruments Q500 TGA, equipped with a 16 position auto-sampler. The instrument was temperature calibrated using certified Alumel. Typically 5-10 mg of each sample was loaded onto a pre-tared platinum crucible and aluminum DSC pan, and was heated at 10°C/min from ambient temperature to 35O 0 C. A nitrogen purge at 60 mL/min was maintained over the sample.
  • PLM Polarized Light Microscopy
  • Hot Stage Microscopy was carried out using a Leica LM/DM polarized light microscope combined with a Mettler-Toledo MTFP82HT hot-stage and a digital video camera for image capture. A small amount of each sample was placed onto a glass slide with individual particles separated as well as possible. The sample was viewed with appropriate magnification and partially polarized light, coupled to a ⁇ false-color filter, whilst being heated from ambient temperature typically at 10°C/min. Melting Point
  • Sorption isotherms were determined on either or both of two instruments. Some were experiments were run using a VTI Corporation SGA-100 moisture sorption analyzer, controlled by VTI FlowSystem 4 software. The sample temperature was maintained at 25°C with the aid of a Polyscience constant temperature bath. The humidity was controlled by mixing streams of dry and wet nitrogen. The weight change as a function of %RH was monitored using a Cahn Digital Recording Balance D-200 with an accuracy of +/-0.0001 g.
  • sample typically a 10-20 mg sample was placed on the tared balance pan under ambient conditions. The sample was dried at 50 0 C for 1 h. The standard adsorption isotherm was performed at 25°C at 5% RH intervals over a 5-95% RH range, and the desorption isotherm was similarly done at 25°C at 5% RH intervals over a 95-5% RH range. Sample equilibration criteria included 0.0100 wt% in 5 min or a maximum equilibration time of 180 min for each %RH data point. Some sorption isotherms were obtained using a Hiden IGASorp moisture sorption analyser, controlled by CFRSorp software.
  • the sample temperature was maintained at 25°C by a Huber re-circulating water bath.
  • the humidity was controlled by mixing streams of dry and wet nitrogen, with a total flow rate of 250 mL/min.
  • the relative humidity was measured by a calibrated Vaisala RH probe (dynamic range of 0-95% RH), located near the sample.
  • the weight change, (mass relaxation) of the sample as a function of % RH was constantly monitored by the microbalance (accuracy ⁇ 0.001 mg).
  • 10-20 mg of sample was placed in a tared mesh stainless steel basket under ambient conditions.
  • the sample was loaded and unloaded at 40% RH and 25 0 C (typical ambient conditions).
  • a moisture sorption isotherm was performed as outlined below (2 scans giving 1 complete cycle).
  • the standard isotherm was performed at 25 0 C at 10% RH intervals over a 0- 90% RH range.
  • the software uses a least squares minimization procedure together with a model of the mass relaxation, to predict an asymptotic value.
  • the measured mass relaxation value must be within 5% of that predicted by the software, before the next % RH value is selected.
  • the minimum equilibration time was set to 1 h and the maximum to 4 h. Typically, samples were recovered after completion of the isotherm and re-analyzed by XRPD. Water Determination by Karl Fischer (KF)
  • Aqueous solubility was determined by suspending sufficient compound in 0.25 ml_ of water to give a maximum final concentration of ⁇ 10 mg/mLof the parent free-form of the compound. The suspension was equilibrated at 25°C for 24 h, and then the pH was measured. The suspension was then filtered through a glass fiber C filter into a 96 well plate. The filtrate was then diluted by a factor of 101. Quantitation was by HPLC with reference to a standard solution of approximately 0.1 mg/mL in DMSO. Different volumes of the standard, diluted and undiluted sample solutions were injected. The solubility was calculated using the peak areas determined by integration of the peak found at the same retention time as the principal peak in the standard injection. If there was sufficient solid in the filter plate, the XRPD was collected.
  • Samples were prepared as 1000 ppm stocks in water. Where sample solubility was low, a suitable co-solvent such as DMSO was used. Samples were diluted to 50 ppm or 100 ppm with an appropriate solvent prior to testing. Quantification was achieved by comparison with standard solutions of known concentration of the ion being analyzed.
  • the liquid chromatography separation was performed using a Waters 2695 Separations Module System with a Waters 2996 Photodiode Array Detector.
  • the positive ion electrospray mass spectrum was obtained using a Waters Micromass ZQ spectrometer fitted with an electrospray source.
  • Example 3 Screen for 1:1 acid addition salts of (2S)-(4E)-N-methyl-5-[3-(5- methoxypyridin)yl]-4-penten-2 -amine
  • Samples of the free base oil were dissolved in each of three solvents (methanol, isopropyl acetate, and dichloromethane) at a concentration of 25 mg/mL. Vials were cooled to 1O 0 C and portions of free base solution equivalent to 30 mg (0.15 mmol) were dispensed into the vials. Various carboxylic acids (1.1 equivalents, 0.165 mmol) were added as either solids or stock solutions. The stock solutions used were either 1.0 M or 0.50 M in THF or THF/water, with the exception of pamoic acid, which was 0.30 M in DMSO. The vials were then capped and the contents stirred at 800 rpm for 2 h.
  • solvents methanol, isopropyl acetate, and dichloromethane
  • salts were found to be solids: hydrochloric acid, sulfuric acid, maleic acid, phosphoric acid, pamoic acid, xinafoic acid (1- hydroxy-2-naphthoic acid), galactaric (mucic) acid, L-tartaric acid, hippuric acid, fumaric acid, citric acid, D-glucuronic acid, L-malic acid, D-gluconic acid, L-ascorbic acid, p-hydroxybenzoic acid, stearic acid (octadecanoic acid), lactobionic acid and orotic acid (uracil-6-carboxylic acid). These salts were analyzed using instrumentation and techniques described in example 2.
  • a stock solution of (2S)-(4E)-N-methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2- amine free base was prepared in acetone at a concentration of 25 mg/mL. Vials were cooled to 10 0 C and portions of free base solution equivalent to 40 mg (0.19 mmol) were dispensed into the vials. Various carboxylic acids (0.6 equivalents, 0.11 mmol) were added as either solids or stock solutions. The vials were then capped and the contents stirred at 800 rpm for 2 h at 50 0 C. After the 2 h period, the reactions were cooled from 5O 0 C to 25 0 C at a rate of 0.4°C/h. Observations were made, and all samples were cooled to 4°C over the next 4 h and stirred at 4°C for a further 2 h.
  • Solid phosphate salts were obtained according to the 1 :1 salt screening procedure, from acetone, isopropanol, acetonitrile or methyl ethyl ketone by evaporation. Ion chromatography established the 1 :1 stoichiometry of these salts. The XRPD diffractograms of these salts are shown in Figure 2.
  • Example 6 (2S)-(4E)-N-Methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2-amine maleate
  • Solid maleate salts were obtained according to the 1:1 salt screening procedure, by precipitation from isopropyl acetate, and from acetone or methyl ethyl ketone by evaporation.
  • the sample was warmed to 5O 0 C and additional isopropyl acetate (4 ml_) was added in an attempt to dissolve the gum. The gum would not dissolve, so it was broken up and stirred.
  • the sample was allowed to cool back to ambient temperature was stored in the refrigerator and then in the freezer. The sample was then equilibrated at room temperature, and the precipitate was collected by suction filtration. The sample was dried in a vacuum oven at 25 0 C to give an off-white powder. NMR analysis established the 1:1 stoichiometry of the salt.
  • a solid xinafoate salt was obtained according to the 1:1 salt screening procedure, from water by evaporation.
  • the XRPD diffractogram of this salt is shown in Figure 5.
  • the hydrochloride salt was obtained according to the 1 :1 salt screening procedure, by precipitation from acetone or isopropanol. Filtration and vacuum drying gave a hygroscopic solid.
  • a solid orotate salt was obtained according to the 1:1 salt screening procedure, by precipitation from isopropyl acetate. NMR analysis established the 2:1 (acid/base) stoichiometry of the salt. The XRPD diffractogram of this salt is shown in
  • Solid pamoate salts were obtained according to the 1:1 salt screening procedure, by precipitation from acetone, toluene/methanol or acetonitrile. Filtration and vacuum drying gave a solid. The XRPD diffractogram of these salts are shown in Figure 8. NMR analysis established the 1 :1 stoichiometry of the salt, as precipitated from acetone.
  • a solid galactarate (mucate) salt was obtained according to the 1:1 salt screening procedure, by precipitation from isopropyl acetate. Filtration and vacuum drying gave a solid which had physical and spectral properties characteristic of a mixture of the hemi-galactarate salt, reported in Example 1 , and free galactaric acid. The mixture was not further characterized.
  • Solid fumarate salts were obtained according to the 1 :1 salt screening procedure, from either isopropyl acetate, dichloromethane, methanol/MTBE or methyl ethyl ketone, by evaporation.
  • the XRPD diffractogram of the salt, from methanol/MTBE, is shown in Figure 9. Chemical analysis indicated that the sample contained impurities resulting from the Michael addition of the secondary amine of the base to the fumaric acid.
  • Example 13 (2S)-(4E)-N-Methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2 -amine stearate
  • Solid stearate salts were obtained according to the 1:1 salt screening procedure, from acetone or isopropyl acetate, by evaporation.
  • the XRPD diffractogram of the salt, from isopropyl acetate, is shown in Figure 10.
  • Solid p-hydroxybenzoate salts were obtained according to the 1:1 salt screening procedure, from isopropyl acetate, by evaporation and from maturation in acetone.
  • the XRPD diffractogram of the salt, form acetone, is shown in Figure 11.
  • the off- white to light beige solids were filtered under a nitrogen atmosphere, washed with MTBE (2 x 25 mL) and vacuum dried at 3O 0 C for -18 h.
  • the yield was 30.39 g of a white to off-white powder.
  • the crude salt was recrystallized by dissolution in acetone (85 mL), assisted by heating to near reflux and the subsequent drop-wise addition of MTBE (170 mL) via addition funnel. After cooling to room temperature and further cooling at 5°C for -18 h, the resulting solids were filtered under a nitrogen atmosphere, washed with MTBE (2 x 25 mL) and vacuum dried at 4O 0 C for -18 h.
  • the di-hydrochloride salt was obtained by mixing an ethanol solution of the (2S)-(4E)-N-methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2-amine with >2 equivalents of concentrated hydrochloric acid and evaporating to dryness (rotary evaporation, followed by high vacuum treatment). The residue was recrystallized from an ethanol/ether mixture to give a white solid, mp 158-16O 0 C. A di-hydrobromide salt (pale yellow solid, mp 87-89 0 C) was isolated in a similar fashion, using hydrobromic acid.
  • Example 19 Polymorph screen for (2S)-(4E)-N-methyl-5-[3-(5- methoxypyridin)yl]-4-penten-2-amine phosphate
  • Form 1 was most common.
  • Forms 2 and 3 were seen only in a few 10 mg scale experiments, and in every case the corresponding scaled up experiments gave only Form 1.
  • the XRPD d iff ractog rams for Forms 1 , 2 and 3, as obtained from this experiment, are shown in Figures 13, 14 and 15 respectively.
  • Form 1 is stable at 4O 0 C and 75% RH for one week (see Figure 16), and is soluble in water at >100 mg/mL It exhibits gain of water at RH values greater than 75%, but this gain of water reversed by lowering the RH.
  • peripheral neuropathy which is indicated by spontaneous pain and the perception of pain from a normally non-noxious stimulation.
  • Streptozotocin (STZ) -induced diabetes in rats is a well-documented model in which a chemotherapeutic drug is administered peripherally, causing irreversible damage to the pancreatic ⁇ and ⁇ cells and inhibiting islet synthesis of proinsulin.
  • the model mimics clinical diabetes and onset of hyperglycemia can be seen in rats within 24 hours.
  • Initial onset of peripheral neuropathy is typically demonstrated in control animals 3-4 weeks following STZ administration.
  • (2S)-(4E)-N-methyl-5-(5-methoxy-3-pyridinyl)-4-pentene-2-amine hemigalactarate was administered acutely and chronically, just before the test at Week 6.
  • (2S)-(4E)-N-methyl-5-(5-methoxy-3-pyridinyl)-4-pentene-2-amine hemigalactarate was evaluated for effects on mechanical allodynia, an assessment of pain response to a normally non-noxious stimulus, in the STZ animal model of peripheral neuropathy.
  • (2S)-(4E)-N-methyl-5-(5-methoxy-3-pyridinyl)-4-pentene-2-amine hemigalactarate was effective in increasing the allodynia threshold in diabetic rats, thereby reducing the pain associated with diabetic neuropathy.
  • (2S)-(4E)-N-methyl-5-(5-methoxy-3- pyridinyl)-4-pentene-2-amine hemigalactarate had a Formula Weight of 311.356 with a salt/base ratio of 1.509.
  • the calculations for total amount of compound needed for the formulary took into account the multiplier of salt/base ratio. Doses are expressed as the free-base equivalents. The materials, once formulated, were considered stable for the entire 6-week period of the study when stored at 4° C.
  • Gabapentin is commonly used as a positive control in neuropathic pain models (Gilron and Flatters, 2006) and has previously been demonstrated to be an effective dose for reversing allodynia in pain models.
  • rats were allocated to treatment groups, twelve (12) rats per group with the exception of satellite groups with six (6) rats in each group, based on baseline allodynia scores collected prior to the start of dosing.
  • the mean allodynia scores for each group were reviewed to ensure that the mean values and standard deviation satisfy the assumption of homogeneity.
  • the animals were acclimated to the allodynia procedure approximately 2 to 3 days prior to testing.
  • the rats were habituated to procedures in the testing devices in order to allow the animals to be calm enough to be properly tested.
  • the rats were placed in a plexiglas cage with a wire mesh bottom and allowed to acclimate for at least 10 minutes. Once the animals were settled, the plantar surface of the right hind paw was touched with a 2.0g von Frey filament. In the absence of a paw withdrawal response to the initially selected filament, a stronger stimulus was presented; in the event of paw withdrawal, the next weaker stimulus was chosen. In this fashion, the resulting pattern of positive and negative responses was used to determine the paw withdrawal threshold, according to the method of Chaplan, et al., 1994. Clinical Health
  • Body weights were measured prior to the start of the study and then weekly during the course of the study. Due to the dehydration and excessive urination associated with this model, all animals were given 5 mL of subcutaneous fluid up to twice daily starting at Day 14.
  • Table B summarizes the percentage of animals that were excluded from the data analysis due to a clear or suspected non-diabetic state based on two sets of blood glucose readings. The first was taken at 4 days post-STZ injection and the second was from blood or plasma that was sampled at approximately 6 wk post-STZ injection. An animal was only accepted as diabetic if it had high (>400 mg/dl) readings for both samples. In the occasional cases where the 6 wk sample was missing, the animal was excluded.
  • Gabapentin At the 6 week timepoint, the mechanical allodynia results for Gabapentin (100 mg/kg; i.p.) demonstrate a significant increase in allodynia thresholds at 0.5 and 2 hr post-dosing as compared to vehicle controls (p ⁇ 0.05; See figure below).
  • (2S)-(4E)-N-methyl-5-(5-methoxy-3-pyridinyl)-4- pentene-2-amine hemigalactarate also demonstrated significant improvement at the 2 hr timepoint post-dosing when the animals were treated either acutely with 1 mg/kg or chronically with 0.03 mg/kg (2S)-(4E)-N-methyl-5-(5-methoxy-3-pyridinyl)-4- pentene-2-amine hemigalactarate(p ⁇ 0.05; See Figure 18). There were no significant effects for other time points or for higher doses of chronically administered (2S)-(4E)- N-methyl-5-(5-methoxy-3-pyridinyl)-4-pentene-2-amine hemigalactarate tested.
  • (2S)-(4E)-N-methyl-5-(5-methoxy-3-pyridinyl)-4-pentene-2-amine hemigalactarate demonstrated a significantly increased allodynia threshold at 2 hr post-dosing (p ⁇ 0.05).
  • (2S)-(4E)-N-methyl-5-(5-methoxy-3-pyridinyl)-4-pentene-2-amine hemigalactarate significantly reversed allodynia at 2 hr post-dosing at 1 mg/kg after acute dosing and also for the low dose (0.03 mg/kg) in the chronic dosing regimen.
  • the reduced group size that resulted from eliminating non-diabetic rats most affected the higher doses of the chronically administered (2S)-(4E)-N-methyl-5-(5- methoxy-3-pyridinyl)-4-pentene-2-amine hemigalactarate groups so it is possible that the chronic dosing actually contributed to the reduced incidence of diabetes in these two treatment groups. It is also the case that these higher doses may have been more likely to demonstrate a significant effect on allodynia had there been a larger sample size in those groups.
  • Peripheral neuropathies are chronic conditions that arise when nerves are damaged by trauma, disease, metabolic insufficiency, or by certain drugs and toxins.
  • the sensory disturbances associated with chemotherapeutic agents, such as Paclitaxel (herein referred to as TAXOL) range from mild tingling to spontaneous burning, typically in the hands and feet. Symptoms become more intense with continued therapy and can lead to weakness, ataxia, numbness, and pain.
  • an animal model of TAXOL-induced sensory neuropathy was employed to evaluate the effects of test compounds for response to tactile sensitivity using the Von Frey test for mechanical allodynia.
  • Animals were administered TAXOL and then dosed with vehicle, acute Gabapentin, or one of three doses of the test compound daily, throughout the course of the study.
  • Testing for mechanical allodynia was performed at three weeks and four weeks post-TAXOL. After the final behavioral test, the sciatic nerve and hind paw were harvested and retained for possible histological analysis. Results demonstrated significant effects of both test compounds in reversing the allodynia levels associated with TAXOL-induced neuropathy.
  • a stock TAXOL solution of 6.0 mg/mL was prepared by the following methods. A quantity of 299.9 mg of TAXOL was weighed on analytical balance and transferred to a container with a stir bar; then 25 mL of Cremaphor (Cremaphor EL, Sigma Aldrich) was added using a syringe and stirred until dissolved; then 25mL of Ethyl alcohol was added and stirred for approximately 5 min. The dosing solution was prepared by diluting the stock solution with deionized water for a concentration of 1 mg/mL. 208.33 mL of saline was added to 41.67 mL of stock TAXOL solution. The Dosing solution was aliquoted into four conical tubes and placed in 2-8 0 C storage until used for dose administration. Animals Animals were obtained, selected, and maintained as indicated in Example 20.
  • Rats were randomly allocated to treatment group based on their baseline Von Frey scores. The group means were reviewed to ensure the mean values and standard deviations satisfied the assumption of homogeneity.
  • rats were allocated to treatment groups, ten (10) rats per group, based on baseline allodynia scores collected prior to the start of dosing. The mean allodynia scores for each group were reviewed to ensure that the mean values and standard deviation satisfied the assumption of homogeneity.
  • Animals in Groups 1-8 were given TAXOL (2mg/kg) i.p. on Days 1, 3, 5 & 7. Animals received daily oral gavage of test compound or vehicle (5 mL/kg), starting the day of the first TAXOL injection and continuing once daily for the entire 4 weeks of the study. On the four days that TAXOL was administered, the test compound was dosed approximately 60 min after TAXOL. The reference compound was given by IP injection at a volume of 2 mL/kg, 90 minutes prior to the allodynia testing only on the day of testing at weeks 3 and 4.
  • the animals were acclimated to the allodynia procedure.
  • the acclimation to the apparatus occurred approximately 2 to 3 days prior to initial testing, as this habituated the rats to the testing devices and allowed the animals to be calm enough to be properly tested.
  • Xf value (in log units) of the final von Frey hair used
  • K value for the pattern of positive/negative responses
  • ⁇ mean difference (in log units) between stimuli.
  • a Bonferroni post-hoc test revealed a significant effect for the 1 mg/kg dose of (2S)-(4E)-N-methyl-5-(5-methoxy-3-pyridinyl)-4-pentene-2-amine hemigalactarate at 3 and 4 weeks (p ⁇ 0.05).
  • (2S)-(4E)-N- methyl-5-(5-methoxy-3-pyridinyl)-4-pentene-2-amine hemigalactarate was effective at 1 mg/kg in reducing allodynia.

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Abstract

L'invention concerne des sels de 2S)-(4E)-n-méthyl-5-[3-(5-méthoxypyridin)yl]-4-pentén-2-amine, des procédés pour leur préparation, des compositions pharmaceutiques comprenant lesdits sels, et leur utilisation. Les sels peuvent être administrés à des patients prédisposés à des affections ou des troubles ou souffrant de ceux-ci, tels que des troubles du système nerveux central, pour traiter ou prévenir de tels troubles.
PCT/US2008/071631 2007-07-31 2008-07-30 Nouvelles formes de sels de (2s)-(4e)-n-méthyl-5-[3-(5-méthoxypyridin)yl]-4-pentén-2-amine WO2009018367A2 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7045538B2 (en) * 1996-04-23 2006-05-16 Targacept, Inc. Compounds capable of activating cholinergic receptors
WO2006053039A2 (fr) * 2004-11-10 2006-05-18 Targacept, Inc. Sels hydroxybenzoates de composes metanicotine

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7045538B2 (en) * 1996-04-23 2006-05-16 Targacept, Inc. Compounds capable of activating cholinergic receptors
WO2006053039A2 (fr) * 2004-11-10 2006-05-18 Targacept, Inc. Sels hydroxybenzoates de composes metanicotine

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
STAHL P H ET AL: "Handbook of Pharmaceutical salts, passage" HANDBOOK OF PHARMACEUTICAL SALTS : PROPERTIES, SELECTION, AND USE, WEINHEIM : WILEY-VCH VERLAG, DE, 1 January 2002 (2002-01-01), pages 329-333,342, XP002472779 ISBN: 978-3-906390-26-0 *
WERMUTH C G ET AL: "Handbook of Pharmaceutical Salts passsage" HANDBOOK OF PHARMACEUTICAL SALTS : PROPERTIES, SELECTION, AND USE, WEINHEIM : WILEY-VCH VERLAG, DE, 1 January 2002 (2002-01-01), pages 1-7, XP002421267 ISBN: 978-3-906390-26-0 *

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